ITMI970047A1 - ANTI-TUBERCULAR PHARMACEUTICAL COMPOSITION AND PROCEDURE FOR ITS PRODUCTION - Google Patents

Description

Description of the invention entitled "ANTITUBERCULAR PHARMACEUTICAL COMPOSITION AND PROCEDURE FOR ITS PRODUCTION"

DESCRIPTION

The present invention relates to an antituberculous pharmaceutical composition in the form of a single-dose tablet comprising four important antituberculous drugs, namely rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride in a combination of fixed dose and a process for the preparation of said antituberculous pharmaceutical composition.

Despite the availability of highly effective treatment regimens for tuberculosis, it remains one of the high-risk diseases in the world and affects adults in their most productive age.

The incidence of tuberculosis is 7.5 million cases in 1990 and India and China account for 44% of the total cases. Tuberculosis cases worldwide are projected to increase by 58% between 1990 and 2005. (Dr. Glenys Bloomfield, Tuberculosis: Trends and opportunities, Scrip Reports 1995).

About 50% of the population of India is believed to be positive for the tuberculin test. 400,000 deaths and one million new cases of tuberculosis are reported annually (TRC Bulletin, Madras, Vol. 1 (2), April 1994). In short, tuberculosis remains India's most important health problem.

The reasons for the increase in the numbers of TB cases are probably due to:

to. epidemic increase in HIV infection.

b. use of indiscriminate and inadequate chemotherapy.

c. resistance to various drugs due to partial addiction to chemotherapy.

d. inadequate bioavailability from pharmaceutically poorly formulated dosage forms.

The failure of antituberculosis therapy is essentially due to the non-compliance or partial non-compliance with the recommended therapy (Tubercle and Lung Disease, Vol. 74, 32-37 (1993)).

Partial addiction to therapy has been found to be a serious threat to the community as the patient taking no therapy transmits non-resistant TB bacilli to other tuberculosis bacilli, while the patient taking partial therapy develops resistance to multiple drugs and transmits bacilli of drug-resistant tuberculosis resulting in a practically incurable form of the disease. One of the approaches used to comply with therapy includes “Directly Observed Therapy” (DOT) which requires complete supervision (New Engl. J. Med., 330, 1179-1184, April 1994).

Other approaches to improving tuberculosis therapy include "Automatic Callback" for appointments at a public TB clinic (Med. Care, 32, 380-389 (4), 1994) and the use of "Calendar Blister Packs" for the treatment of tuberculosis, to improve adaptation to therapy (Lancet 335: 473, 1990).

To control the re-emergence of drug-resistant tuberculosis, the World Health Organization has presented a set of instructions for the effective treatment of tuberculosis. Among other things, the WHO recommends "Short Chemotherapy" (SCC) with emphasis on simplicity and usability. This therapy consists of two phases. The initial phase consists of four drugs, namely rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride administered daily to two months and the second phase or continuation phase consists of two drugs, namely isoniazid and rifampicin administered daily or intermittently. However, it has been observed that, in developing countries, and with short-term chemotherapy, the cure quotient does not reach 85% The main reason for these modest results is the patient's poor adaptation to the prescribed treatment regimen.

Although significant improvements in adaptation to therapy have been observed, as a result of these concepts, some specific drawbacks such as high cost of supervision, impracticality in rural areas and selective discontinuation of some medicines are associated with these approaches. Hence, to improve patient adaptation, minimize drug resistance and ease of administration; WHO, Center for Disease Control (CDC), International Union Against Tuberculosis & Lung Disease (JUATLD) and American Thoracic Society have recommended the use of a fixed combined dose (Tubercle and Lung Disease 75: 180-181 (1994) and Ann. Intern. Med., 122: 951-954 (1995)).

Fixed-dose combinations of rifampicin with isoniazid alone (two-drug fixed dose) or with pyrazinamide and isoniazid (three-drug fixed dose) are commercially available. An article by S. Afr. Med. J., 86 (2), 155 (1996) illustrates the study of the early bactericidal activity of a fixed combination of isoniazid, rifampicin and pyrazinamide (rifater) in patients with pulmonary tuberculosis.

In the United States Pharmacopoeia (USP 23, 1995), capsules containing rifampicin in combination with isoniazid are described. However, the USP specifies an upper limit over the label indications of 110% for capsules containing rifampicin alone, while for the combined formulation, the upper limit for rifampicin is 130%, indicating some stability overdose for rifampicin. .

However, the fixed-dose combination of rifampicin along with isoniazid, pyrazinamide, and ethanbutol hydrochloride, which are basic drugs in brief chemotherapy of tuberculosis and included in many multidrug regimens recommended by WHO et al. (Guidelines for National Programs, WHO, 1993; New Engl. J. Med., Vol. 329, n ° 11, 1993; AM. Pharm. NS26: 12, October 1986; J. Infect. Dis. 159: 96-100, January 1989; Ann. Int. Med.

117-257, August 1992; Principles of Therapy of Tuberculosis in the Modern Era, chapter 60, 751-762) has not been described so far.

Solid state rifampicin alone is stable but its stability in the presence of moisture and other anti-tuberculosis drugs is questionable. Hence the instability of rifampicin with isoniazid in liquid dosage form, reported in East Pharma, 33: 139-40, 1990. Furthermore, rifampicin is passable to oxidation and is known to degrade in the presence of moisture and, being the ethanbutol hydrochloride is a highly hydroscopic product, this tends to catalyze this decomposition. As a result of these specific difficulties, the production of a stable pharmaceutical formulation of the four primary anti-tuberculosis drugs in the form of a fixed dose tablet has not been achieved so far.

Regardless of the aforementioned problems of obtaining a stable fixed dose combination of the above four primary antituberculosis drugs, it has also been found difficult to obtain such a fixed dose combination of said drugs in tablet dosage form, for the following reasons:

There are three main methods for tableting, namely wet granulation, dry granulation and direct compression.

The dry granulation method comprises sieving of drugs and excipients followed by granulation of the resulting powder mixture by compression in the absence of heat and solvent. This is the least desirable method (Pharmaceutical Dosage Forms: Tablets vol. I, p.

173, ed. by H.A. Lieberman & L. Lachman, Pub. Mercel Dekkar Ine. (1980)).

The direct compression method provides a process in which the tablets are obtained by directly compressing the drug and excipients mixtures without any pre-treatment and the disadvantages are the separation of the components of the mixture and also the formation of dust (The Pharmaceutical Codex, Principle and Practice of Pharmaceutics, page 10, ed. by W. Lund, Pub. the Council of the Royal Pharmaceutical Society of Great Britain).

The direct compression method was found to be unsuitable for the preparation of a pharmaceutical composition of the four anti-tuberculosis drugs due to the poor flow of the mixture and the high doses of active ingredients with consequent problems of coverage (i.e. the top of the tablet remains cracked around the edge or separated as a cap) that occur during tableting.

The wet granulation process is a process in which drugs and excipients are screened and the resulting particles are adhered to each other with the use of an adhesive to produce a granular product with improved flow properties and a greater capacity to flow. cohesion under pressure. Furthermore, formulations prepared by wet granulation have a lower tendency to demix.

The wet granulation method is advantageous over other methods in terms of high volume production, uniform particle size distribution, as well as providing a homogeneous mixture with free flowing properties and improved compressibility. Another advantage is that it requires a drying cycle to produce a dry granulate with a low moisture content. Low humidity (1-3%) is desirable for greater stability (cited work).

In consideration of these and other needs for industrial production, wet granulation becomes the method of choice.

The fundamental object of the present invention is therefore to provide a stable antituberculous pharmaceutical composition in the form of fixed dosage tablets, containing all four basic antituberculous drugs, i.e. rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride, as a fixed dose combination of said drugs. .

Another object of the present invention is to provide a wet granulation process for the preparation of an antituberculous pharmaceutical composition in the form of fixed dose tablets by tableting the four important antituberculous drugs, i.e. rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride, in a fixed dose combination.

Yet another object of the present invention is to provide a wet granulation process for the preparation of an antituberculous pharmaceutical composition in the form of fixed dose tablets containing the four antituberculous drugs, to obtain a physically and chemically stable and bioavailable product.

According to another object of the present invention, this provides a stable antituberculous pharmaceutical composition in a fixed dose tablet form comprising all four major antituberculous products, i.e. rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride, as a fixed dose combination of said drugs. .

A further object of the present invention is to provide an antituberculous pharmaceutical composition in the form of a fixed dose tablet containing the four important antituberculous drugs, i.e. rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride in a fixed dose combination which is stable at high temperature storage. and relatively high humidity.

Still another object of the present invention is to provide an antituberculous pharmaceutical composition in the form of a fixed dose tablet comprising the four antituberculous drugs to obtain a bioavailable, physically and chemically stable product.

According to an aspect of the present invention, a process is therefore provided for the production of a pharmaceutical composition in the form of a fixed dose tablet containing the four anti-tuberculosis drugs rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride, comprising:

a) mixing rifampicin and ethanbutol hydrochloride with the excipients then wet granulating the resulting mixture with a binder so as to obtain granules of said mixture and subsequently drying said granules;

b) mixing isoniazid and pyrazinamide with excipients and then wet granulating the resulting mixture with a binding product to obtain granules of said mixture and subsequently drying said granules;

c) mixing the granules thus obtained in steps (a) and (b) above, with excipients to obtain a lubricated mixture with the same composition;

d) converting the resulting lubricated mixture into tablets containing said fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride;

e) coat the tablets obtained in step (d) above.

According to another aspect of the present invention, a process is provided for the production of a pharmaceutical composition in fixed dosage tablets containing four anti-tuberculosis drugs, i.e. rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride, comprising:

a) mixing the rifampicin with the excipients and wet granulating the resulting mixture with a binding product to obtain granules of said mixture, then drying;

b) mixing isoniazid, pyrazinamide and ethanbutol hydrochloride with excipients, then wet granulating the resulting mixture with a binding product to obtain granules of said mixture and subsequently drying said mixed granules;

c) mixing the granules thus obtained in steps (a) and (b) above, with excipients, to obtain a lubricated mixture;

d) converting the resulting lubricated mixture to tablets containing said fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride;

e) coat the tablets obtained in step (d) above.

In the process described above according to the invention, the excipients used include one or more antioxidants, inert diluents, surfactants and conventional additives such as lubricating and opacifying agents.

The present invention therefore provides a wet granulation process for the preparation of a pharmaceutical composition in tablet dosage form, comprising four important antituberculous drugs, i.e. rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride in a fixed dose combination together with excipients. , pharmaceutically acceptable binders and stabilizers.

The above described process according to the invention thus solves the problems associated with the manufacture of a stable tablet dosage form containing all four basic and aforementioned anti-tuberculosis drugs, according to the wet granulation technique widely practiced for such preparations.

According to another aspect of the present invention, an antituberculous pharmaceutical composition is provided in the form of a fixed dose tablet, containing:

i) a granulated mixture of rifampicin and ethanbutol hydrochloride with separation barrier coatings, and ii) a granulated mixture of isoniazid and pyrazinamide also equipped with barrier coatings, said tablet having a homogeneous content of:

a) rifampicin from 75 mg to 300 mg;

b) isoniazid from 75 mg to 150 mg;

c) pyrazinamide from 250 mg to 1000 mg;

d) ethanbutol hydrochloride from 200 mg to 600 mg; and e) excipients comprising said barrier coating products such as those described herein with or without other conventional additives.

According to still another aspect of the present invention, an antituberculous pharmaceutical composition is provided in the form of a fixed dose tablet, comprising:

i) granulated rifampicin having a barrier coating, and ii) a granulated mixture of ethanbutol hydrochloride, isoniazid and pyrazinamide also having a barrier coating, said tablet dosage form having a homogeneous content of:

a) rifampicin from 75 mg to 300 mg;

b) isoniazid from 75 mg to 150 mg;

c) pyrazinamide from 250 mg to 1000 mg;

d) ethanbutol hydrochloride from 200 mg to 600 mg; and e) excipients, including said barrier coating products as described herein with or without other conventional additives.

In the anti-tuberculosis pharmaceutical composition described above, according to the invention, the excipients, apart from said barrier coating material, further comprise one or more binding materials, antioxidants, inert diluents, surfactants, lubricants and opacifiers in an amount from 200 mg to 716 mg.

The antituberculous pharmaceutical composition of the present invention is in the form of a dosed tablet whereby it contributes to a precise dosage for rapid administration and strongly encourages patient adaptation. The process of the present invention ensures a suitable formulation and preparation of the composite of the first four antituberculous drugs, which is stable, highly concentrated and with a convenient tablet dosage form.

The inert diluents which can be used in the process and included in the pharmaceutical composition of the present invention are calcium carbonate, calcium sulfate, dextrans, dibasic calcium phosphate, hydrogenated vegetable oils, magnesium carbonate, magnesium oxide, mannitol, microcrystalline cellulose, polymethacrylates, cellulose powder, pregelatinised starch, sorbitol, starch, tribasic calcium phosphate. However, the preferred diluents are microcrystalline cellulose and starch.

The surfactants that can be used are anionic surfactants such as sodium docusate (dioctyl sodium sulfosuccinate), sodium lauryl sulfate or non-ionic surfactants such as glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80 or polyvinyl alcohol. The preferred surfactants of the present invention are sodium lauryl sulfate and sodium docusate.

The antioxidants which can be used in the process of the invention are ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium metabisulphite. The preferred antioxidant is ascorbic acid.

Excipients preferably suitable for the process of the invention comprise one or more of ascorbic acid, magnesium stearate, microcrystalline cellulose, colloidal silicon dioxide, talc and sodium lauryl sulfate.

The binding products suitable for use in the process and included in the pharmaceutical composition of the invention are binders commonly used for wet granulation, such as gum arabic, alginic acid, carbomers, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, oil hydrogenated vegetable, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, aluminum and magnesium silicate, methyl cellulose, polymethacrylate, povidone, pregelatinised starch, sodium alginate, starch, zein. The preferred binder for the rifampicin granules is starch paste and for the other parts it is gelatin.

Preferably, the binder product used comprises any one or more of starch paste, crospovidone and gelatin solution in quantities ranging from 45.23 g to 120.94 g for starch paste, 124.38 g and 221.73 g for crospovidone and from 33.03 g and 60.47 g for the gelatin solution in the pharmaceutical composition according to the invention.

Conventional additives which may be used include coating agents, coloring agents and the like.

Suitable coating agents for use are sodium carboxymethyl cellulose, carnauba wax, cellulose acetate phthalate, cetyl alcohol, sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polymethacrylate, zein, shellac, polyvinyl alcohol , microcrystalline wax and Tabcoat TC-MB. Preferred coating agents are Tabcoat TC-MB, hydroxypropyl methylcellulose, and ethylcellulose. Tabcoat TC-MB is the most preferred coating agent as it provides a better moisture barrier. The coating composition may contain plasticizers such as benzyl benzoate, chlorine butanol, dibutyl sebacate, glycerin, mineral and vegetable oils, lanolin alcohols, polyethylene glycols, propylene glycol, sorbitol, triacetin, triethyl citrate; opacifiers such as titanium dioxide, talc, colloidal silicon dioxide and other ingredients such as dyes. Preferred ingredients in the coating composition are castor oil, talc, colloidal silicon dioxide and titanium dioxide as well as coating agents. Iron oxide is the preferred dye.

The stability of rifampicin in combination with the other antituberculous drugs, obtained in the dosage form in tablets by the process of the invention and that obtained with granulation and tableting processes other than those of the invention is evaluated at high temperature (60 ° C) and high relative humidity (40 ° C / 75%) by exposing the granules in a petri dish for 24 hours, then the results are presented in the following Table 1.

TABLE 1

P C l%

The results of Table 1 clearly show the stability and consequent acceptability of the dosage form in tablets of the combination of said four main antituberculous drugs only in the case in which a drug in said tablet form is obtained following the process of the invention. It is also evident, from Table 1, that the best results according to the process of the invention are obtained when rifampicin and ethanbutol hydrochloride are first granulated and subsequently mixed with granules containing isoniazid and pyrazinamide. This preferred method of preparation in the invention is further confirmed by the following:

rifampicin and ethanbutol hydrochloride are mixed in a tray or planetary mixer with an inert diluent such as microcrystalline cellulose, an antioxidant such as ascorbic acid and a surfactant such as sodium lauryl sulfate, and the resulting mixture is granulated with 20% starch pulp, drying the resulting granules up to a moisture content of the mixture equal to 1-3%. Isoniazid and pyrazinamide are mixed with the microcrystalline cellulose and starch and granulated with gelatin and the resulting granules are dried until the moisture content is between 1 and 3%. Both granules are mixed with microcrystalline cellulose, pregelatinised starch, crospovidone and lubricated with colloidal silicon dioxide, talc and magnesium stearate. This forms a barrier between rifampicin and other anti-tuberculosis drugs, in particular isoniazid. The lubricated mixture is tableted with a suitable load to form tablets (using a sixteen-station rotary tablet press from Cadmach (India)) on a daily regimen of 2 to 4 doses.

The tablets are coated with a moisture barrier coating of Tabcoat TC-MB with iron oxide.

The tablets are found to have contents of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride including between 90 and 110% of the label indication, i.e. no overdose is added, which is a marked improvement over the prior art.

The film-coated tablets thus obtained according to the present invention are evaluated with various tests, as follows:

1. Hardness:

The hardness of the tablets is more than 4 kg / cm2.

2 . Disintegration test:

The disintegration test is less than 30 minutes.

3. In vitro dissolution test:

In vitro dissolution rate test in 900 ml of enzyme-free artificial gastric fluid, with a vane system at 50 g / min and 37 ° C, more than 75% of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride dissolve after 30 minutes.

4. Chemical stability of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride:

Rifampicin is analyzed by high resolution reversed phase liquid chromatography (RP-HPLC) using a 250 x 4 mm column loaded with 5 μm octylsilane and UV detection at 250 nm. Isoniazid and pyrazinamide are analyzed simultaneously with the same principle, column and detection, however with a different mobile phase. Ethanbutol is extracted with chloroform and then determined by non-aqueous titration with perchloric acid.

The product is stable when stored under accelerated conditions at a temperature between 40 and 45 ° C and with 75% relative humidity for over three months in tear-off aluminum packs.

5. Bioequivalence study:

The bioequivalence study of the four antituberculosis drugs combined in the film-coated fixed-dose tablet is compared with that of single drug dosage forms containing the same amounts of drug. The study is carried out on twelve healthy male volunteers aged between 20 and 40 who are fasted for 10 hours. The blood is drawn at regular intervals for 24 hours and the serum is separated. The serum is analyzed by HPLC to determine rifampicin, isoniazid and pyrazinamide and by GC-ECD to determine ethanbutol hydrochloride.

The difference between the serum concentration of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride between the single dose formulation and the fixed combination dose products is statically insignificant and the relative bioavailability of the fixed dose product is comparable to the drug formulations. single. The summary of the pharmacokinetic parameters is shown in the following Table 2:

TABLE 2

COMPARATIVE BIOEQUIVALENCE DATA

Cmax: maximum concentration obtained

Tmax: time needed to reach the maximum level of drug in the blood

AUC: area under the curve {bioavailability) The present invention therefore provides a wet granulation procedure for the preparation of the pharmaceutical composition comprising the four important antituberculous drugs, in which the composition remains unchanged for longer times and also avoids the use of overdose.

Furthermore, the present invention provides a pharmaceutical composition which includes all four important antituberculosis drugs, wherein the composition remains unaffected by longer times and also avoids the use of overdose.

The objects of the invention, its advantages and its embodiment are described in more detail below with reference to non-limiting exemplary embodiments.

Example 1:

Rifampicin (450 g) and ethanbutol hydrochloride (800 g) are mixed with microcrystalline cellulose (60 g), ascorbic acid (9 g), sodium lauryl sulfate (15 g) for 15-30 minutes in a planetary or paddle mixer. The mixture is granulated with 60 g of starch (in the form of a 20% paste) and dried at 55-65 ° C until the moisture content is between 1 and 3%. 300 g of isoniazid and 1500 g of pyrazinamide are mixed separately with microcrystalline cellulose (210 g) and starch (90 g) for 15-30 minutes in a planetary or paddle mixer, and the resulting mixture is then granulated with 45 g of solution gelatin (7.5%) and dried at 55-65 ° C until the moisture content is between 1 and 3%. Both granules are mixed with microcrystalline cellulose (315 g) and crospovidone (165 g) for 5-15 minutes in a planetary or paddle mixer. To the mixture obtained, colloidal silicon dioxide (18 g), talc (39 g) and magnesium stearate (39 g) are added and it is mixed for a further 5-10 minutes. The lubricated mixture is compressed with a suitable load to obtain tablets with a daily administration regimen of 2 to 4 doses. Since the composition is moisture sensitive, the tablets are coated with a moisture barrier coating of Tabcoat TC-MB (176.25 g) and iron oxide (30 g). Tabcoat TC-MB is a ready-made coating composition consisting of hydroxypropyl methylcellulose, ethylcellulose, castor oil, talc, colloidal silicon dioxide and titanium dioxide and has good moisture barrier properties.

Film-coated tablets are analyzed for hardness, disintegration test, in vitro dissolution test, chemical stability and bioequivalence.

All the physico-chemical parameters were satisfactory. The hardness of the tablets is more than 4 kg / cm <2>. The disintegration time is less than 30 minutes and more than 75% of the rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride dissolve after 30 minutes in the in vitro dissolution test. The contents of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are between 90 and 110% of the label indication. The product is stable (no significant changes in physico-chemical parameters) for storage under accelerated conditions (45 ° C and 40 ° C / 75% relative humidity) for over 3 months in tear-off aluminum packaging. The difference between the serum concentration of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride for single drug formulations and fixed dose combination products is statically insignificant and the relative bioavailability of the fixed dose product is comparable to that of the drug formulations. single. Bioequivalence data are presented in Table 2.

Example 2:

Rifampicin (300 g) and ethanbutol hydrochloride {800 g) are mixed with microcrystalline cellulose (45.23 g), ascorbic acid (6.78 g), sodium lauryl sulfate (11.30 g) for 15-30 minutes in a blender planetary or vane. The mixture is granulated with 45.23 g of starch (in the form of a 20% paste) and dried at 55-65 ° C until the moisture content is 1-3%. Isoniazid (200 g) and pyrazinamide (1000 g) are mixed separately with microcrystalline cellulose (158.30 g) and starch (67.84 g) for 15-30 minutes in a planetary or paddle mixer, and the resulting mixture is then granulated with 33.92 g of gelatin solution (7.5%) and dried at 55-65 ° C to a moisture content between 1 and 3%. Both granules are mixed with microcrystalline cellulose (237.46 g) and crospovidone (124.38 g) for 5-15 minutes in a planetary or paddle mixer. Colloidal silicon dioxide (13.56 g), talc (29.40 g) and magnesium stearate (29.40 g) are added to the above mixture and it is mixed for 5-10 minutes. The lubricated mixture is tableted at a suitable pressure obtaining tablets for a daily drug regimen of 2 to 4 doses. Since the composition is sensitive to moisture, the tablets are coated with a moisture barrier coating of Tabcoat TC-MB (176.25 g) and iron oxide (30 g).

The film-coated tablets are tested for hardness, disintegration test, chemical stability and in vitro dissolution.

All the physico-chemical parameters are satisfactory.

The hardness of the tablets is greater than A kg / cm <2>. Over 75% of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride dissolve after 30 minutes in the in vitro dissolution test. The contents of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are between 90 and 110% of the label indications. The product is stable (no significant change in physicochemical parameters) when stored under accelerated conditions (45 ° C and 40 ° C / 75% relative humidity) for over 3 months in tear-off aluminum packaging.

Example 3:

Rifampicin (600 g) and ethanbutol hydrochloride (1200 g) are mixed with microcrystalline cellulose (80.62 g), ascorbic acid (12.09 g) and sodium lauryl sulfate (20.15 g) for 15-30 minutes in a blender planetary or vane. The mixture is granulated with 80.62 g of starch (in the form of a paste at 20%) and dried at 55-65 ° C until reaching a moisture content between 1 and 3%. Isoniazid (300 g) and pyrazinamide (2000 g) are mixed separately with microcrystalline cellulose (282.20 g) and starch (120.94 g) for 15-30 minutes in a planetary or paddle mixer, and the resulting mixture is then granulated with 60.47 g of gelatin solution (7.5%) and dried at 55-65 ° C to a moisture content between 1 and 3%. Both granules are mixed with microcrystalline cellulose (423.30 g) and crospovidone (221.73 g) for 5-15 minutes in a planetary or paddle mixer. Colloidal silicon dioxide (24.18 g), talc (52.40 g) and magnesium stearate (52.40 g) are added to the above mixture and it is mixed for 5-10 minutes. The lubricated mixture is tableted at a suitable pressure obtaining tablets for a daily drug regimen of 2 to 4 doses. Since the composition is moisture sensitive, the tablets are coated with a moisture barrier coating of Tabcoat TC-MB (176.25 g) and iron oxide (30 g).

The film-coated tablets are tested for hardness, disintegration test, chemical stability and in vitro dissolution.

All the physico-chemical parameters are satisfactory. The hardness of the tablets is more than 4 kg / cm <2>. 75% of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride dissolve after 30 minutes in the in vitro dissolution test. The contents of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are between 90 and 110% of the quantity indicated on the label. The product is stable (no significant change in physico-chemical parameters) when stored under accelerated conditions (45 ° C and 40 ° C / 75% relative humidity) for over 3 months in tear-off aluminum packaging. Example 4:

Rifampicin (450 g) is mixed with 60 g of microcrystalline cellulose, 9 g of ascorbic acid and 15 g of sodium lauryl sulfate for 15-30 minutes in a planetary or paddle mixer. The mixture is granulated with 60 g of starch (in the form of a 20% paste) and dried at 55-65 ° C to a moisture content between 1 and 3%. Isoniazid (300 g), pyrazinamide (1500 g) and ethanbutol hydrochloride (800 g) with microcrystalline cellulose (210 g) and starch (90 g) are mixed separately for 15-30 minutes in a planetary or paddle mixer, and the resulting mixture it is then granulated with 45 g of gelatin solution (7.5%) and dried at 55-65 ° C until the moisture content is between 1 and 3%. Both granules are mixed with microcrystalline cellulose (315 g) and crospovidone (165 g) for 5-15 minutes in a planetary or paddle mixer. Colloidal silicon dioxide (18 g), talc (39 g) and magnesium stearate (39 g) are added to the above mixture and mixed for 5-10 minutes. The lubricated mixture is compressed with an appropriate load to obtain tablets for a daily dosing regimen of 2 to 4 doses. Since the composition is moisture sensitive, the tablets are coated with a moisture barrier layer of Tabcoat TC-MB (176.25 g) and iron oxide (30 g).

The film-coated tablets are tested for hardness, disintegration test, chemical stability and in vitro dissolution.

All the physico-chemical parameters are satisfactory. The hardness of the tablet is higher than 4 kg / cm2. 75% of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride dissolve after 30 minutes in the in vitro dissolution test. The contents of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are between 90 and 110% of the label indications. The product is stable (no significant change in physico-chemical parameters) when stored under accelerated conditions (45 ° C and 40 ° C / 75% relative humidity) for over 3 months in tear-off aluminum packaging.

Example 5:

Rifampicin (300 g) is mixed with microcrystalline cellulose (45.23), ascorbic acid (6.78 g), sodium lauryl sulfate (11.30 g) for 15-30 minutes in a planetary or paddle mixer. The mixture is granulated with 45.23 g of starch (in the form of a paste at 20%) and dried at 55-65 ° C to a moisture content between 1 and 3%. Isoniazid (200 g), pyrazinamide (1000 g) and ethanbutol hydrochloride (800 g) with microcrystalline cellulose (158.30 g) and starch (67.84 g) are mixed separately for 15-30 minutes in a planetary or paddle mixer, and the resulting mixture is then granulated with 33.92 g of gelatin solution (7.5%) and dried at 55-65 ° C to a moisture content between 1 and 3%. Both granules are mixed with microcrystalline cellulose (237.46 g) and crospovidone (124.38 g) for 5-15 minutes in a suitable mixer such as a planetary or paddle mixer. Colloidal silicon dioxide (13.56 g), talc (29.40 g) and magnesium stearate (29.40 g) are then added to the above mixture and the mixture is mixed again for 5-10 minutes. The lubricated mixture is tableted with an appropriate load resulting in tablets for a daily dosing regimen of 2 to 4 doses. Since the composition is moisture sensitive, the tablets are coated with a moisture barrier coating of Tabcoat TC-MB (176.25 g) and iron oxide (30 g).

Film-coated tablets are tested for hardness, disintegration test, chemical stability and in vitro dissolution.

All the physico-chemical parameters are satisfactory. The hardness of the tablet is greater than 4 kg / cm <2>. The disintegration time is less than 30 minutes and more than 75% of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride dissolve after 30 minutes in the in vitro dissolution test. The contents of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are between 90 and 110% of the label indications. The product is stable (no significant changes in physico-chemical parameters) when stored under accelerated conditions (45 ° C and 40 ° C / 75% relative humidity) for over 3 months in tear-off aluminum packaging.

Example 6:

Rifampicin (600 g) is mixed with microcrystalline cellulose (80.62 g), ascorbic acid (12.09 g), sodium lauryl sulfate (20.15) for 15-30 minutes in a planetary or paddle mixer. The mixture is granulated with 80.62 g of starch (in the form of a paste at 20%) and dried at 55-65 ° C to a moisture content of between 1 and 3%. Isoniazid (300 g), pyrazinamide (2000 g) and ethanbutol hydrochloride (1200 g) with microcrystalline cellulose (282.20 g) and starch (120.94 g) are mixed separately for 15-30 minutes in a planetary or paddle mixer, and the resulting mixture is then granulated with 60.47 g of gelatin solution (7.5%) and dried at 55-65 ° C to a moisture content of between 1 and 3%. Both granules are mixed with microcrystalline cellulose (423.30 g) and crospovidone (221.73 g) for 5-15 minutes in a planetary or paddle mixer. Colloidal silicon dioxide (24.18 g), talc (52.40 g) and magnesium stearate (52.40 g) are then added to the above mixture and it is mixed for 5-10 minutes. The lubricated mixture is tableted with an appropriate load to obtain tablets for a daily dosing regimen of 2 to 4 doses. Since the composition is moisture sensitive, the tablets are coated with a moisture barrier coating of Tabcoat TC-MB (176.25 g) and iron oxide (30 g).

The film-coated tablets are tested for hardness, disintegration test, chemical stability and in vitro dissolution.

All the physico-chemical parameters are satisfactory. The hardness of the tablets is more than 4 kg / cm <2>. The disintegration time is less than 30 minutes and over 75% of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are dissolved after 30 minutes in the in vitro dissolution test. The contents of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are between 90 and 110% of the label indication. The product is stable (no significant change in physico-chemical parameters) when stored under accelerated conditions (45 ° C and 40 ° C / 75% relative humidity) for over 3 months in tear-off aluminum packaging.

Example 7:

The same procedure of Example 1 is repeated, except that rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are granulated separately. The film-coated tablets are satisfactory in every respect. The hardness of the tablets is more than 4 kg / cm2. The disintegration time is less than 30 minutes and more than 75% of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are dissolved after 30 minutes in the in vitro dissolution test; the contents of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are between 90 and 110% of the label indications. The product is stable (no significant changes in physico-chemical parameters) for storage under accelerated conditions (45 ° C and 40 ° C / 75% relative humidity) for over 3 months in an aluminum tear-off packaging. Example 8:

The same procedure of Example 1 is repeated, except that rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride are granulated together.

Film coated tablets are found to have unsatisfactory stability when evaluated for chemical stability.

Example 9:

The same procedure of Example 1 is repeated, except that rifampicin is mixed with isoniazid and granulated; pyrazinamide and ethanbutol hydrochloride are granulated together.

Film coated tablets are found to have unsatisfactory stability when tested for chemical stability.

Example 10:

The same procedure of Example 1 is repeated, except that all the antituberculous drugs, ie rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride, as well as the excipients are mixed together and compacted. The compacted mixture is lubricated and tableted. The mixture is unsuitable for compression on a rotary tablet press. There are problems with compression of the pads (cover).

Example 11:

The procedure of Example 1 is repeated, except that the sodium lauryl sulfate is replaced with polysorbate 80.

The film-coated tablets are found to have unsatisfactory stability in the chemical stability test.

Claims (38)

CLAIMS 1. Process for the production of an antituberculous pharmaceutical composition in the form of a fixed dose tablet, containing the four antituberculous drugs rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride comprising: a) mixing rifampicin and ethanbutol hydrochloride with excipients and then wet granulating the resulting mixture with a binding product in order to obtain granules of said mixture and subsequently subjecting to said granules to drying; b) mixing isoniazid and pyrazinamide with excipients, then wet granulating the resulting mixture with a binding product to obtain granules of said mixture and subsequently drying said granules; c) mixing the granules thus obtained in steps (a) and (b) above, with excipients to obtain a lubricated mixture of the same granules; d) converting the resulting lubricated mixture into tablets containing said fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride; e) coat the tablets obtained in step (d) above. 2. Process for the production of an antituberculous pharmaceutical composition in the form of fixed dose tablets, containing the four antituberculous drugs rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride, comprising: a) mixing rifampicin with excipients and then wet granulating the resulting mixture with a binder for obtaining granules of said mixture and then drying them; b) mixing isoniazid, pyrazinamide and ethanbutol hydrochloride with excipients, then wet granulating the resulting mixture with a binding product to obtain granules of said mixture and drying said mixed granules; c) mixing the granules obtained in steps (a) and (b) above, with excipients to obtain a lubricated mixture; d) transforming the resulting lubricated mixture into tablets containing said fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride; e) coat the tablets obtained in step (d) above. Process according to any one of claims 1 or 2, wherein said coating comprises coating with a solution containing the coating and coloring agents. 4. Process according to any one of claims 1 or 3, wherein said excipients are selected from one or more antioxidants, inert diluents, surfactants, lubricating and opacifying agents. 5. Process according to claim 4, wherein the inert diluent is selected from any one or more of calcium carbonate, calcium sulfate, dextrates, dibasic calcium phosphate, hydrogenated vegetable oil, magnesium carbonate, magnesium oxide, mannitol, microcrystalline cellulose, polymethacrylates, powdered cellulose, pregelatinized starch, sorbitol, starch, tribasic calcium phosphate and preferred diluents are microcrystalline cellulose and starch. 6. Process according to any one of claims 4 or 5, wherein the surfactant is selected from one or more of anionic surfactants such as sodium docusate, sodium lauryl sulfate and non-ionic surfactants such as glyceryl monooleate, polysorbate 80, polyvinyl alcohol, and the preferred they are sodium lauryl sulfate and sodium docusate. 7. Process according to any one of claims 4 to 6, wherein the antioxidant is selected from any one or more of ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, propyl gallate, sodium ascorbate, sodium metabisulfite, and the most preferred is ascorbic acid. 8. Process according to claim 1, wherein said binder used in step (a) to obtain the granules of rifampicin and ethanbutol hydrochloride is made of starch and said binder used in step (b) to obtain granules of isoniazid and pyrazinamide is solution of jelly. 9. Process according to claim 2, wherein the binder used in step (a) to obtain rifampicin granules is starch paste and the binder used in step (b) to obtain isoniazid, pyrazinamide and ethanbutol hydrochloride granules is gelatin solution . 10. Process according to any one of claims 1 to 7, wherein said binder is selected from one or more of gum arabic, alginic acid, carbomers, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, aluminum magnesium silicate, methylcellulose, polymethacrylate, povidone, pregelatinised starch, sodium alginate, starch, zein. 11. Process according to any one of claims 1 to 10, wherein said granule mixing step (c) is carried out in a paddle mixer. Process according to any one of claims 2 to 10, wherein said granule mixing step (c) is carried out in a paddle mixer. 13. Process according to any one of claims 1 to 12, wherein said excipient used is selected from one or more of ascorbic acid, magnesium stearate, microcrystalline cellulose, colloidal silicon dioxide, talc and sodium lauryl sulfate. 14. Process according to any one of claims 1 to 13, wherein said binder used is selected from starch paste, gelatin solution and crospovidone. 15. Process according to any one of claims 3 to 14, wherein the coating agent is selected from any one or more of castor oil, talc, colloidal silicon dioxide, titanium dioxide, sodium carboxymethyl cellulose, carnauba wax, acetate cellulose phthalate, cetyl alcohol, sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polymethacrylate, zein, shellac, polyvinyl alcohol, microcrystalline cellulose, plasticizers such as benzyl benzoate, chlorine butanol , glycerin, mineral and vegetable oils, lanolin, alcohols, polyethylene glycol, propylene glycol, sorbitol, triacetin, triethyl citrate and opacifiers. 16. Process according to any one of claims 7 to 15, wherein the ascorbic acid used is comprised between about 5 mg and about 50 mg per gram of rifampicin. 17. Process according to any one of claims 3 to 16, wherein said dye used is ferric oxide. A process according to any one of claims 1 to 17, wherein said step of transforming the resulting lubricated mixture into tablets comprises subjecting said resulting lubricated mixture to a compression step to produce said tablets. 19. Process according to claim 18, in which said compression step is carried out in a tablet press machine, preferably a sixteen-station rotary machine for tableting tablets. Process according to any one of claims 1 to 19, wherein said drying step of said granules produced in steps (a) and (b) comprises drying in the temperature range between 55 and 65 ° C. 21. Process according to any one of claims 1 to 20, wherein said drying of the granules is carried out until a moisture content between 1 and 3% is reached. A process for producing a pharmaceutical tablet composition according to any one of claims 1 to 21, wherein each tablet produced contains an amount of rifampicin between about 75 mg and about 300 mg, an amount of isoniazid between about 75 mg and about 150 mg, an amount of pyrazinamide between about 250 mg and about 1000 mg, ethanbutol hydrochloride between about 200 mg and about 600 mg and excipients in a quantity between about 200 mg and about 716 mg. 23. Antituberculosis pharmaceutical composition in fixed dosage tablet form, comprising: i) granulated mixture of rifampicin and ethanbutol hydrochloride with a barrier coating and ii) granulated mixture of isoniazid and pyrazinamide also equipped with a barrier coating, said dosage tablet having a homogeneous content of: a) from 75 mg to 300 mg of rifampicin; b) from 75 mg to 150 mg of isoniazid; c) from 250 mg to 1000 mg of pyrazinamide; d) from 200 mg to 600 mg of ethanbutol hydrochloride; And e) excipients comprising said barrier coating material such as that described herein, with or without other conventional additives. 24. Pharmaceutical composition antituberculosis in the form of a fixed dosage tablet, comprising: i) granulated rifampicin with a barrier coating, and ii) granulated mixture of ethanbutol hydrochloride, isoniazid and pyrazinamide also equipped with a barrier coating, said dosage tablet having a homogeneous content of: a) from 75 mg to 300 mg of rifampicin; b) from 75 mg to 150 mg of isoniazid; c) from 250 mg to 1000 mg of pyrazinamide; d) from 200 mg to 600 mg of ethanbutol hydrochloride; And e) excipients, including said barrier coating material as described herein, with or without other conventional additives. 25. Antituberculosis pharmaceutical composition according to any one of claims 23 or 24, wherein said excipients comprise one or more of antioxidants, inert diluents, binders and surfactants, in an amount from 200 mg to 716 mg. 26. Antituberculosis pharmaceutical composition according to claim 25, wherein said inert diluent comprises one or more of calcium carbonate, calcium sulfate, dextrose, dibasic calcium phosphate, hydrogenated vegetable oil, magnesium carbonate, magnesium oxide, mannitol, cellulose microcrystalline, polymethacrylates, powdered cellulose, pregelatinized starch, sorbital, starch, tribasic calcium phosphate and the preferred diluents are microcrystalline cellulose and starch. 27. Antituberculosis pharmaceutical composition according to any one of claims 25 or 26, wherein said surfactant comprises one or more anionic surfactants such as sodium docusate, sodium lauryl sulfate and non-ionic surfactants such as glyceryl monooleate, polysorbate 80 and polyvinyl alcohol and the preferred ones are lauryl sulfate sodium and docusate sodium. 28. Antituberculosis pharmaceutical composition according to any one of claims 25 to 27, wherein said antioxidant comprises one or more of ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, propyl gallate, sodium ascorbate, sodium metabisulfite and the preferred one is 1 'ascorbic acid. 29. Antituberculosis pharmaceutical composition according to any one of claims 25 to 28, wherein said binder comprises one or more of gum arabic, alginic acid, carbomers, sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose , hydroxypropyl cellulose, hydroxypropylmethyl cellulose, aluminum and magnesium silicate, methyl cellulose, polymethacrylate, povidone, pregelatinised starch, sodium alginate, starch and zein. 30. Antituberculosis pharmaceutical composition according to any one of claims 23 to 29, wherein said conventional additives comprise one or more of coating agents and dyes. 31. An antituberculous pharmaceutical composition according to claim 30, wherein said coating agent comprises any one or more of castor oil, talc, colloidal silicon dioxide, titanium dioxide, sodium carboxymethyl cellulose, carnauba wax, cellulose phthalate acetate, alcohol cetyl, sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polymethacrylate, zein, shellac, polyvinyl alcohol, microcrystalline cellulose, plasticizers such as benzyl benzoate, chlorobutanol, dibutyl seberine and vegetables, lanolin, alcohols, polyethylene glycol, propylene glycol, sorbitol, triacetin, triethyl citrate and opacifiers. 32. Antituberculous pharmaceutical composition according to any one of claims 25 to 31, wherein said antioxidant comprises ascorbic acid in an amount of 0.02 to 0.1 mg per gram of rifampicin. 33. Antituberculous pharmaceutical composition according to any one of claims 31 or 32, wherein said coloring agent comprises ferric oxide. 34. Pharmaceutical antituberculosis composition according to any one of claims 23 to 33, wherein said excipients comprise one or more of ascorbic acid, in an amount from 6.78 g to 12.09 g, magnesium stearate, in an amount from 29.40 g to 52 , 40 g, microcrystalline cellulose, in quantities from 45.23 g to 423.20 g, colloidal silicon dioxide, in quantities from 13.56 g to 58 g, talc, in quantities from 29.40 g to 52.40 g, and lauryl sodium sulphate in quantities ranging from 11.30 g to 20.15 g. 35. Antituberculosis pharmaceutical composition according to any one of claims 25 to 34, wherein said binder comprises one or more starch paste, in an amount from 45.23 g to 120.94 g, crospovidone, in an amount from 124.38 g to 221, 73 g, and gelatin solution, in quantities of 33.03 g and 60.47 g. 36. An antituberculosis pharmaceutical composition according to any one of claims 30 to 35, wherein said coating agents comprise a moisture barrier coating consisting of Tabcoat TC-MB and iron oxide. 37. Process for the production of a pharmaceutical composition in the form of a dosage tablet, containing a fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride, which exhibits excellent stability and bioequivalence substantially in the manner described here and illustrated with reference to the examples. 38. Pharmaceutical antituberculosis composition in dosage tablet form comprising rifampicin, isoniazid, pyrazinamide and ethanbutol hydrochloride, substantially as described herein and illustrated with reference to the illustrated examples.